2015.4.1 Presenter:尤鈺婷 Supervisor:劉清泉, 吳凱文 Intern seminar Mycobacterium bovis BCG-Associated Osteomyelitis(MBBO) 2015.4.1 Presenter:尤鈺婷 Supervisor:劉清泉, 吳凱文

Outline Case presentation Discussion Mycobacterium genus Normal response of BCG vaccine 4 Most Common Adverse Effect of BCG M. bovis BCG osteomyelitis(MBBO) Incidence Pathogenesis Diagnosis Clinical features Treatment Compensation in Taiwan Take home message References

Age: 2year-1-month-old female Date of admission: 2015/3/11. Patient profile Name:鄭O晴 ID:16822xx5 Age: 2year-1-month-old female Date of admission: 2015/3/11. Chief complaint Progressive BCG vaccination site swelling with pus formation for 7 months 16822555

Present Illness 2013/1/17 NSD 嘉義基督教醫院 35-day-old 嘉基 BCG Vaccination, a small area of redness No post-injection fever, lymphadenopathy 8 month-old A raised nodule about the size of a soybean Tenderness(-), erythematous change(-) 使用項目符號並逐字討論 所有細節。 Went to clinic at 金門, suggested observation

History of present illness Pustule, tenderness 1year-6-month-old 嘉基suggest observation 2015/2/23 2 year-1-month-old 嘉基ER Drainage about 10ml and sent for culture 嘉基 OPD Culture: no growth Gram stain(-); acid fast stain(-) Suspected BCG skin infection INAH(?),Suggested Excision 2015/2/26 2 year-1-month-old 使用項目符號並逐字討論 所有細節。

3/11 At NCKU 1.5cm*0.6cm, well-defined, rubbery, pustule tenderness

X-ray –Lateral view Relatively osteosclerotic change with focal linear radiolucent chnage at the metaphysis of proximal humerus. R L

X Ray-AP view R L

Biopsy 3/12 Surgery finding: Fistula with flank pus deep to deltoid fascial layer 3 sets of tissue

Tentative Diagnosis and Treatment Tentative Diagnosis Left humeral head osteomyelitis, suspect Mycobacterium bovis BCG vaccination related Treatment Isoniazid 150mg QD Rifamicin 150mg QD Moxifloxacin 100mg QD Relatively osteosclerotic change with focal linear radiolucent chnage at the metaphysis of proximal humerus.

Pathology and Culture (1)Bacterial Gram stain: Negative Culture: Negative (2)Mycobacterial Acid-fast stain: Negative TB-PCR: Negative Culture: Pending (3)Pathology Fibrosis. The specimen is limited (4)台灣CDC 分子鑑定 :MTBC (-) No evidence of suppurative or granulomatous inflammation is found.

Compared Between 3 Cases of M. bovis BCG Infection location Left upper arm Right upper chest Right thumb onset 8 month 2Y3M 2Y1M Appearance 8 month-elevated, soybean like 20-month erythematous, pustule 1.5*0.6cm well-demarcated, non-erythematous, tenderness 1.5*3cm erythematous, swelling, ill-demarcated

鄭O晴♀ 曾O涵♀ 吳O彣♂ location Left upper arm Right upper chest Right thumb X-ray Osteolytic change osteosclerotic change with focal linear radiolucent change

鄭O晴♀ 曾O涵♀ 吳O彣♂ location Left upper arm Right upper chest Right thumb pathology Inadequate bony tissue granulomatous inflammation CDC analysis MTBC(-) M. Bovis BCG M. Bovis BCG Current status s/p 1-year-medication Regular follow up Still in treatment

曾O涵♀at chest wall osteolytic bone lesion at anterior end of right 3rd rib. Imp: Osteomyelitis at right anterior 3rd rib with perilesional abscess formation. DDs: a) TB b) Fungal infection c) Bacterial (less likely)

曾O涵♀at chest wall Lobulated soft tissue mass below right pectoralis muscle, 43x27x24mm in size, with inner marginal enhanced cystic component, causing right 3rd rib expansile appearance with focal cortical destruction.

吳O彣♂right thumb

吳O彣♂right thumb s/p surgery&1 month medication Before surgery s/p 2 month medication s/p 3 month medication

Complication of BCG-vaccination Discussion Complication of BCG-vaccination

M. Tuberculosis complex (MTBC) Mycobacteria Genus Mycobacteria genus(分枝桿菌屬) can be divided into 3 groups, M. tuberculosis complex(MTBC結核菌群),Nontuberculous Mycobacteria(非結 核菌群) and M. leprae(麻風桿菌) M. Tuberculosis complex (MTBC) Japan : multiplepuncture(subq) R. Brosch et al. PNAS 2002; 99

M. Bovis BCG strain type Japan : multiplepuncture(subq) Taiwan and Japan is currently using Tokyo 172 strain. Sun Myung Joung, et al. Clin Exp Vaccine Res 2013;2:83-91

Normal response of BCG vaccine (1)<3 weeks, erythematous induration (2) 6 weeks, bluish-purple pustule (3)10 weeks, ulceration (4)3 months healing Image: Cape Town . G Hussey

4 Most Common Adverse Effect of BCG Local abscess (2)Lymphadenitis (3)Osteomyelitis (4)Disseminated infection

Incidence of M. bovis-BCG Osteomyelitis-Worldwide According to WHO, the estimated rate of osteomyelitis is 1–700 per million with different strain-derived BCG. In Scandinavia the incidence rate was 64 per million. In Japan, the incidence rate was 0.01 per million. Spacer oligonucleotide typing (spoligotyping)是一種利用PCR(polymerase chain reaction)為基礎的分析方法。 Chiu NC et al. Taiwan Emerg Infect Dis. 2015 Mar So Hee Kim et al. Vaccine 26 (2008)

Incidence of M. bovis-BCG Osteomyelitis-Taiwan (4)Incidence of BCG osteomyelitis increased from 3.68 cases per million vaccinations during 2002–2006 to 30.1 per million during 2008–2012. Spacer oligonucleotide typing (spoligotyping)是一種利用PCR(polymerase chain reaction)為基礎的分析方法。 Chiu NC, et al. Taiwan Emerg Infect. 2015 Mar

M. bovis-BCG Osteomyelitis Diagosis (1)Method used to identify Tokyo-172 vaccine strain was established in 2004. (2)衛生署疾病管制局衛署疾管核字第0990007683號來函： 通報單純肺外結核病人之病理檢體應施行耐酸性染色及結 核菌培養，15歲以下個案之培養陽性之菌株或無法培養出 菌株之病理檢體（如有病理檢體報告請一併檢附），連同 防疫檢體送驗單送疾病管制局昆陽辦公室研究檢驗中心分 枝結核桿菌實驗室進行卡介苗鑑定 行政院衛生署疾病管制局衛署疾管核字第 0990007683號來函表示如下： 通報單純肺外結核病人之病理檢體應施行 耐酸性染色及結核菌培養，15歲以下個案 之培養陽性之菌株或無法培養出菌株之 病理檢體（如有病理檢體報告請一併檢 附），連同防疫檢體送驗單送疾病管制局 昆陽辦公室研究檢驗中心分枝結核桿菌實 驗室進行卡介苗鑑定， Jou R, et al Taiwan. Emerg Infect Dis. 2009;15:1525–6. Jou R, 結核病最新治療指引. CDC Taiwan

M. bovis-BCG Osteomyelitis Diagosis 3)衛生署疾病管制局 肺外結核病人之病理檢體應施行耐酸性染色及結核菌培養，15歲以下個案之培養陽性之菌株或無法培養出菌株之病理檢體（如有病理檢體報告請一併檢附），連同防疫檢體送驗單送疾病管制局昆陽辦公室研究檢驗中心分枝結核桿菌實驗室進行卡介苗鑑定

BCG Infected Patient Identified by CDC Taiwan(2005-2007) Spacer oligonucleotide typing (spoligotyping)是一種利用PCR(polymerase chain reaction)為基礎的分析方法。 8 osteomyelitis, 3 suppurative lymphadenitis, 1 injection site abscess,2 subQ abscess away from injection site, 1 disseminated Jou R et al. Emerg Infect Dis. 2009;15:1525–6

Pathogenesis of BCG osteomyelitis (1)Unknown (2)Risk factor were identified as strain type, the method of vaccination. (3)Possible pathogenetic mechanisms are direct BCG inoculation and haematogenous spread. PK Chan, et al.Hong Kong Med J. 2010 Jun;16(3):223-6.

Clinical Features of BCG-Osteomyelitis (1) Symptoms began 3–32months after BCG vaccination and are usually insidious. (2)80% involved extremity bones. 20% involved axial bones. Tibia>ankle>femur (3) Blood cell counts and inflammation markers showed no specific abnormalities. Spacer oligonucleotide typing (spoligotyping)是一種利用PCR(polymerase chain reaction)為基礎的分析方法。 Chiu NC et al. Taiwan Emerg Infect. 2015 Mar

Clinical Features of BCG-Osteomyelitis (4)Active phase, osteolytic change Ghamar Taj Khotaei, et al. J Microbiol Immunol Infect2006;39:169-172

Treatment of BCG-Osteomyelitis (1)Diagnostic biopsy Wide excision is not indicated & (2)Anti-TB medication(12months) Isoniazid +   Rifamicin +Moxifloxacin (3)M. bovis BCG is resistant pyrazinamide  pza Chii-Jeng Lin, J of bone &joint surgery, 1999 Sep; 81 (9): 1305 -11

Ranking of Compensation for Vaccine Adverse Effect in Taiwan 1988 年成立預防接種受害救濟基金 我國的疫苗受害救濟給付件數及金額以BCG 最多 係因我國衛生單位針對BCG 不良反應進行主動監測及鑑定方 法的確認，使得不良反應案件與疫苗之相關性亦獲得確認而予給付 我國衛生所及合約醫療院所辦理預防接種業務與申請受害救濟案件分析, CDC疫情報導

How Could We Help 結核病個案管理制度 之內涵及運作, Taiwan CDC

Take Home Messages BCG vaccine may cause severe adverse reactions, such as abscess, lymphadenitis, BCG-osteomyelitis and disseminated BCG infection. Incidence of BCG osteomyelitis increased after establishment of the active reporting system of vaccine adverse events by the public and medical institutes. BCG osteomyelitis has good clinical outcome and surgery is usually not needed.

References R. Brosch et al. A new evolutionary scenario for theMycobacterium tuberculosis complex, PNAS 2002; 99 Sun Myung Joung, et al. BCG vaccine in Korea, Clin Exp Vaccine Res 2013;2:83-91 Chiu NC, et al. Mycobacterium bovis BCG–associated osteomyelitis/osteitis, Taiwan. Emerg Infect Dis.2015 Mar So Hee Kim, et al. BCG osteomyelitis caused by the BCG Tokyo strain and confirmed by molecular method, Vaccine 26 .2008 Jou R, et al. Tokyo-172 BCG vaccination complications, Taiwan. Emerg Infect Dis. 2009;15:1525–6 Chii-Jeng Lin, et al. Mycobacterium bovis Osteomyelitis as a Complication of Bacille Calmette-Guérin (BCG) Vaccination: Rapid Diagnosis with Use of DNA Sequencing Analysis, J of bone &joint surgery, , 1999 Sep; 81 (9): 1305 -11 我國衛生所及合約醫療院所辦理預防接種業務與申請受害救濟案件分析, CDC疫情報導 結核病個案管理制度 之內涵及運作, Taiwan CDC Jou R, 結核病最新治療指引. CDC Taiwan

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